Dr. Neilson is a trained developmental immunologist/mouse geneticist who has used the first portion of his postdoctoral fellowship in Phillip A. Sharp's lab at the the MIT Center for Cancer Research to gain a deeper understanding of short RNA biology, as well as to become facile with in vitro experimental approaches. Dr. Neilson's objective is to head an academic laboratory at a top research institution. During the mentored phase of the award period, Dr. Neilson aims to strengthen his exposure to the fields of biochemistry and bioinformatics. Training in the latter field in particular is increasingly important. During the mentored phase of the proposal, Dr. Neilson will generate mice with conditional alleles of the miR-92-1 locus. He will also initiate a biochemical characterization of the oncogenic miR-17-92 cluster as outlined in the proposal. Dr. Sharp's ability to mentor this mode of experimentation is unparalleled. Simultaneously, Dr. Neilson will take academic and non-academic courses to become fluent in programming and bioinformatic approaches, and teach an advanced undergraduate course in short RNAs and immunology. MIT and the Center for Cancer research have outstanding core facilities and academic resources relevant to these purposes. Once the mentored phase has been completed, Dr. Neilson and his trainees will continue the characterization of the mouse mutants proposed herein. Dr. Neilson's newly acquired biochemical and bioinformatic skill sets will be used in parallel with his existing knowledge of mammalian development and immunology to characterize the consequences of miR-92-1 disruption at the phenotypic, biochemical, and genomic levels. The consequences of miR-92-1 disruption in the context of the biochemical experiments performed during the mentored phase will be examined. The discovery of gene regulation by a new class of genes termed miRNAs has fundamentally changed the scientific view of how cells control gene expression. Several of these genes have been implicated in cancer. A detailed understanding how miRNAs work and how they themselves are controlled will allow a fuller comprehension of mammalian biology, at the same time enabling more effective exploitation of the pathway giving rise to these genes for therapeutic purposes (RNAi).